Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis.

中文翻译：

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源自患者的 GBM 肿瘤球体的分泌组分析将中期因子鉴定为有效的治疗靶点。

胶质母细胞瘤 (GBM) 是最致命的原发性脑肿瘤，几乎没有治疗选择。胶质瘤起始细胞 (GIC) 的存活是导致治疗失败的主要因素之一。GIC 经常产生并响应其自身支持细胞增殖和存活的生长因子。在这项研究中，我们旨在确定介导 GIC 存活的关键自分泌因素，并评估拮抗这些因素的抗 GBM 作用。在生长因子耗尽状态下，使用来自两种不同患者来源的 GBM 肿瘤球体的条件培养基进行蛋白质组学分析。然后，通过生物信息学分析和分子验证评估抑制已确定的自分泌因子的抗肿瘤作用。形成球体的 GIC 分泌的蛋白质可促进细胞增殖/存活并解毒活性氧 (ROS)。在这些蛋白质中，我们专注于中期因子 (MDK) 作为一种具有临床意义和病理相关的自分泌因子。拮抗 MDK 通过促进细胞周期停滞和随后由氧化应激诱导的 DNA 损伤引起的凋亡细胞死亡来降低 GBM 肿瘤球的存活率。我们还确定了 PCBP4，这是一种新的抗 MDK 治疗抗性分子预测因子。总的来说，我们的结果表明，MDK 抑制是一种重要的治疗选择，通过诱导 ROS 介导的细胞周期停滞和细胞凋亡来抑制 GIC 存活。拮抗 MDK 通过促进细胞周期停滞和随后由氧化应激诱导的 DNA 损伤引起的凋亡细胞死亡来降低 GBM 肿瘤球的存活率。我们还确定了 PCBP4，这是一种新的抗 MDK 治疗抗性分子预测因子。总的来说，我们的结果表明，MDK 抑制是一种重要的治疗选择，通过诱导 ROS 介导的细胞周期停滞和细胞凋亡来抑制 GIC 存活。拮抗 MDK 通过促进细胞周期停滞和随后由氧化应激诱导的 DNA 损伤引起的凋亡细胞死亡来降低 GBM 肿瘤球的存活率。我们还确定了 PCBP4，这是一种新的抗 MDK 治疗抗性分子预测因子。总的来说，我们的结果表明，MDK 抑制是一种重要的治疗选择，通过诱导 ROS 介导的细胞周期停滞和细胞凋亡来抑制 GIC 存活。